New cephalosporin antibiotics substituted directly on the C.sub.3 carbon atom of the cephem nucleus with methoxy and halo groups are described by R. R. Chauvette and P. A. Pennington, J. Am. Chem. Soc., 96, 4986 (1974). As described therein, the 3-halo and 3-methoxy-substituted-cephalosporins are prepared from 3-exomethylenecepham esters by ozonolysis of the 3-exomethylene double bond. The product of the ozonlysis, a 3-"oxo" 3-cephem ester, is characterized as a 3-hydroxy-3-cephem ester which can also exist in its tautomeric keto form. The 3-methoxy substituted cephalosporin is prepared by reacting the 3-hydroxy-3-cephem ester with diazomethane while the 3-halo cephalosporin is prepared by halogenating the 3-hydroxy ester intermediate.
The 3-exomethylenecepham cephalosporin esters employed as starting materials in the synthesis of the 3-halo and 3-methoxy substituted cephalosporins are described in J. Org. Chem., 38, 2994 (1973).
Accordingly, the 3-hydroxy-3-cephem esters are valuable intermediates useful in the preparation of the 3-methoxy and 3-halo cephalosporin antibiotic compounds.
In the co-pending application of R. R. Chauvette Ser. No. 310,191 filed Nov. 28, 1972, now U.S. Pat. No. 3,917,587 the ozonolysis of 3-exomethylenecepham esters to 3-hydroxy-3-cephem esters is described. The 3-exomethylenecepham esters, employed as starting materials in the process have the sulfur of the dihydrothiazine ring in the sulfide or unoxidized divalent state. The 3-hydroxy-3-cephem ester products obtained in the disclosed process also have the sulfur atom of the dihydrothiazine ring in the divalent unoxidized state, and suffer from certain disadvantages. For example, they tend to undergo over-oxidation during the ozonolysis to form the corresponding sulfoxide. The presence of the sulfoxide complicates the isolation and purification of the 3-hydroxy-3-cephem ester product. Further, the 3-hydroxy-3-cephem esters exhibit instability. Consequently, when used as intermediates to the 3-methoxy or 3-halo antibiotics, the 3-hydroxy-3-cephem esters are best employed soon after their preparation and isolation in the described process.